Over half of all new cancers are skin cancers and its incidence is on the rise due to increased recreational exposure to sunlight and depletion of the ozone layer (American Cancer Society's 2004 Facts & Figures; Nataraj, et al. (1995) Photochem. Photobiol. 62:218-230; McKenzie, et al. (1999) Science 285:1709-1711). While the use of sunscreens has decreased the risk of skin cancers (Stern, et al. (1986) Arch. Dermatol. 122:537-545; Glanz, et al. (2002) Morbid. Mortal. Wkly. Rep. 51:1-18), there is a need to identify additional approaches for skin cancer prevention in individuals previously exposed to high-dose levels of sunlight.
Treatment of SKH-1 hairless mice with ultraviolet B (UVB) (30 mJ/cm2) twice a week for 20 weeks results in mice without tumors but with epidermal hyperplasia and a high risk of developing skin tumors during the next several months in the absence of further UVB treatment (Lou, et al. (1999) Nutr. Cancer 33:146-153). This animal model resembles humans who have received high levels of exposure to sunlight early in life with reduced exposure later in life. UVB-pretreated high-risk mice have been used for evaluating the effects of potential chemopreventive agents on skin tumor formation in the absence of further exposure to UVB. Oral administration of green tea, black tea, or caffeine to UVB-pretreated high-risk mice inhibits tumorigenesis, but the decaffeinated teas have little or no activity, and reconstitution of the decaffeinated teas with caffeine restores biological activity (Lou, et al. (1999) Nutr. Cancer 33:146-153; Lu, et al. (2001) Cancer Res. 61:5002-9; Huang, et al. (1997) Cancer Res. 57:2623-9). Further, oral administration of black tea to UVB-pretreated mice with tumors selectively inhibits the growth of the tumors by inhibiting proliferation and stimulating apoptosis in the tumors without affecting normal non-UVB-treated skin (Lu, et al. (1997) Carcinogenesis 18:2163-2169). Oral administration of green tea or caffeine for two weeks prior to a single irradiation with UVB also enhances UVB-induced increases in epidermal wild-type p53 and apoptosis in the epidermis of SKH-1 mice (Lu, et al. (2000) Cancer Res. 60(17):4785-91). In addition, topical application of caffeine to the skin of SKH-1 mice, immediately after irradiation with UVB, decreases the number of nonmalignant and malignant skin tumors (Lu, et al. (2002) Proc. Natl. Acad. Sci. USA 99:12455-60) and enhances apoptosis as evidenced by increases in caspase 3 (active form)-immunoreactive-positive cells and caspase 3 enzyme activity in the epidermis (Lu, et al. (2002) Oncol. Res. 13:61-70). Similarly, local application of caffeine and theophylline to Swiss (Carshalton) mice reduces the incidence of skin cancer induced by repeated irradiation with UV light (Zajdela and Latarjet (1978) Natl. Cancer Inst. Monogr. (50):133-40).
U.S. Pat. No. 6,642,274 further teaches that caffeine and other methylated xanthines are useful in the prevention and treatment of prostate disorders including benign prostatic hypertrophy and carcinoma of the prostate.
Moreover, U.S. Pat. No. 6,316,435 teaches methods and kits for treating lymphoproliferative diseases in a host including administering to a host pentostatin, at least one alkylating agent and at least one methylated xanthine.